Stereospecific Synthesis of Optically Active Phenylpropylene Oxides

Dipartimento Farmaco-Chimico, Universita` di Bari, Via E. Orabona 4, I-70126 - Bari, ... Chimica dei Composti OrganoMetallici “ICCOM”, Sezione di ...
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Stereospecific Synthesis of Optically Active Phenylpropylene Oxides Vito Capriati, Saverio Florio,* Renzo Luisi, and Irene Nuzzo Dipartimento Farmaco-Chimico, Universita` di Bari, Via E. Orabona 4, I-70126 - Bari, CNR, Istituto di Chimica dei Composti OrganoMetallici “ICCOM”, Sezione di Bari, Italy [email protected] Received December 22, 2003

The stereospecific lithiation of diastereomeric phenylpropylene oxides has been studied as well as the trapping reaction with electrophiles. The reduction of the cis-R-benzoylpropylene oxide to give prevalently the anti-epoxy alcohol has been investigated as well. Introduction Optically active phenylpropylene oxides are highly versatile building blocks for asymmetric syntheses.1 Indeed, they have been successfully employed for the design of silica-supported dendritic chiral catalysts2 and as key intermediates in the stereoselective construction of multisubstituted tetrahydrofurans3a whose unit occurs frequently in natural products, e.g., antibiotics and C-glycosides.3b Phenylpropylene oxides are usually made by asymmetric epoxidation of trisubstituted olefins1b with chiral (salen)Mn(III) complexes,4 ketone catalysts,5 dioxiranes,6 and functionalized iminium salt systems,7 whereas the corresponding chiral nonracemic epoxy alcohols, which are valuable molecules for the preparation of biologically active compounds such as β-blockers,8 can be prepared by the Sharpless-Katsuki epoxidation9 or by using a chiral Fe(porph)oxo complex.10 The oxiranyl anion-based methodology has undoubtedly become a valuable method for making functionalized epoxides. Stabilized and nonstabilized oxiranyl anions, * To whom correspondence should be addressed. Phone: +39805442749. Fax: +39805442231. (1) (a) Besse, P.; Veschambre, H. Tetrahedron 1994, 50, 8885-8927. (b) Bonini, C.; Righi, G. Tetrahedron 2002, 58, 4981-5021. (c) Behrens, C. H.; Katsuki, T. Coord. Chem. Rev. 1995, 140, 189-214. (2) Chung, Y.-M.; Rhee, H.-K. Catal. Lett. 2002, 82, 249-253. (3) (a) A synthesis of enantiomerically pure substituted tetrahydrofurans, promoted by organoselenium reagents, from optically active 1-phenylpropylene oxides has been recently described: Tiecco, M.; Testaferri, L.; Bagnoli, L.; Purgatorio, V.; Temperini, A.; Marini, F.; Santi, C. Tetrahedron: Asymmetry 2004, 15, 405-412. (b) Kamimura, A.; Mitsudera, H.; Matsuura, K.; Omata, Y.; Shirai, M.; Yokoyama, S.; Kakehi, A. Tetrahedron 2002, 58, 2605-2611. (4) (a) Brandes, B. D.; Jacobsen, E. N. J. Org. Chem. 1994, 59, 43784380. (b) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343, 5-26. (5) Tian, H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002, 67, 2435-2446. (6) (a) Denmark, S. E.; Wu, Z. J. Org. Chem. 1998, 63, 2810-2811. (b) Denmark, S. E.; Wu, Z. Synlett 1999, 847-859. (7) Page, P. C. B.; Rassias, G. A.; Barros, D.; Ardakani, A.; Buckley, B.; Bethell, D.; Smith, T. A. D.; Slawin, A. M. Z. J. Org. Chem. 2001, 66, 6926-6931. (8) Hansen, R. M. Chem. Rev. 1991, 91, 437-475. (9) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237-6240. (10) Adam, W.; Prikhodovski, S.; Roschmann, K. J.; Saha-Mo¨ller C. R. Tetrahedron: Asymmetry 2001, 12, 2677-2681.

mainly oxiranyllithiums, made available by deprotonation, transmetalation, desilylation, desulfinylation, or via a carbenoidic route, have been rather deeply studied and synthetically exploited for the preparation of target molecules.11 Our involvement in the oxiranyl anion methodology12a-e has recently led us to discover that R-lithiated styrene oxides are chemically and configurationally stable so that they can be stereospecifically captured with electrophiles. Such a methodology has been successfully applied to the synthesis of optically active epoxylactones12f and a potent oral antifungal agent.12g Relying on the synthetic efficiency of the above-mentioned oxiranyl anion methodology, we decided to extend our investigation to the lithiation of cis- and transphenylpropylene oxides and to the use of the resulting lithiated species for the synthesis of more substituted stereodefined phenylpropylene oxides. Herein, we report the first stereospecific synthesis of trisubstituted phenylpropylene oxides based on the deprotonation-alkylation (hydroxylalkylation) of the simpler and easily available chiral nonracemic cis- and trans-phenylpropylene oxides. Results and Discussion Highly enantiomerically enriched (1S,2S)-(-)-1-phenylpropylene oxide 1a, commercially available (ee 99%), can be eventually prepared (76% yield, ee g 95% in our hands) from (1S,2R)-(+)-N-methylephedrine according to (11) For some recent reviews on oxiranyl anions, see: (a) Satoh, T. Chem. Rev. 1996, 96, 3303-3325. (b) Mori, Y. Rev. Heteroatom Chem. 1997, 17, 183-211. (c) Hodgson, D. M.; Gras, E. Synthesis 2002, 12, 1625-1642. (d) Florio, S., Ed. Oxiranyl and aziridinyl anions as reactive intermediates in synthetic organic chemistry. Tetrahedron 2003, 59, 9683-9864. (12) (a) Abbotto, A.; Capriati, V.; Degennaro, L.; Florio, S.; Luisi, R.; Pierrot, M.; Salomone, A. J. Org. Chem. 2001, 66, 3049-3058 and references therein. (b) Capriati, V.; Favia, R.; Florio, S.; Luisi, R. ARKIVOC 2003, (xiv), 77-86. (c) Luisi, R.; Capriati, V.; Carlucci, C.; Degennaro, L.; Florio, S. Tetrahedron 2003, 59, 9707-9712. (d) Luisi, R.; Capriati, V.; Degennaro L.; Florio, S. Tetrahedron 2003, 59, 97139718. (e) Luisi, R.; Capriati, V.; Degennaro L.; Florio, S. Org. Lett. 2003, 5, 2723-2726. (f) Capriati, V.; Degennaro, L.; Favia, R.; Florio, S.; Luisi, R. Org. Lett. 2002, 4, 1551-1554. (g) Capriati, V.; Florio, S.; Luisi, R.; Salomone, A. Org. Lett. 2002, 4, 2445-2448. 10.1021/jo035858w CCC: $27.50 © 2004 American Chemical Society

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Published on Web 04/13/2004

Synthesis of Optically Active Phenylpropylene Oxides SCHEME 1a

SCHEME 2

TABLE 1. Reaction of (1S,2S)-2a with Electrophiles

a Reagents and conditions: (i) s-BuLi/TMEDA, THF, -98 °C, 2 h for (1S,2S)-1a, 30 min for (1S,2R)-1b; (ii) electrophile.

electrophile

product (% yield)a

convn (%)

D2O CH3I CH2dCHCH2Br (CH3)2CO

(1S,2S)-3a (77) (2S,3S)-3b (51) (4S,5S)-3c (74) (3S,4S)-3d (51)

>98 >98 98 83

drb

erc

>98:2 >99:1 ” ” ” 97:3 ” >99:1

[R]20Dd -38.0 -16.0 +6.6 +7.0

a Isolated yield after distillation or column chromatography. Diastereomeric ratio determined by 1H NMR analysis of the crude reaction mixture. c Enantiomeric ratio by GC analysis on a Chiraldex B-DM capillary column. d c 1, CHCl3.

Castedo’s procedure,13 which uses a phase-transfer catalyst. Racemic 1a has been prepared by an in situ (CF3COCH3)-catalyzed epoxidation of trans-β-methylstyrene (H2O2 as primary oxidant at high pH), as reported by Shi.14 (1S,2R)-(-)-1-Phenylpropylene oxide 1b has been analogously synthesized (95% yield, ee g 95%) starting from (1S,2S)-(+)-N-methylpseudoephedrine13 and racemic 1b by reduction of 1-phenyl-1-propyne,15 followed by the oxidation of the resulting cis-β-methylstyrene according to Shi’s procedure (62% overall yield).14 Treatment of a precooled mixture (-98 °C) of (1S,2S)(-)-1-phenylpropylene oxide 1a (ee 99%) and TMEDA (3 equiv) in THF with s-BuLi (3 equiv) (n-BuLi and LDA were ineffective) gave a cherry-red solution likely to be ascribed to the lithiooxirane 2a, which proved to be chemically stable at low temperature (-98 °C) for at least 2 h. The trapping reaction of 2a with a deuterium source (D2O) furnished the corresponding R-deuterated phenylpropylene oxide in a good yield after distillation (77%, > 98% D): the reaction took place with complete retention of configuration at the R-carbon (dr >98:2, ee >98%),16 thus indicating that 2a is also configurationally stable (Scheme 1). The use of less than 3 equiv of either the base or TMEDA as well as a shorter reaction time led only to lower deuterium incorporation, but the observed diastereo- and enantioselectivity was still very high. Compared to the lithiation of the unsubstituted styrene oxide,12g the epoxide 1a, probably for steric reasons,17 underwent a slower R-deprotonation, but the resulting lithiated species showed a longer lifetime (2 h) (lithiated styrene oxide showed a lifetime of only 30 min).12g Here again, as in

the case of lithiation of styrene oxide, the presence of TMEDA and of a donor solvent (THF) was unavoidable; in fact, the use of a nondonor solvent (hexane), the absence of TMEDA, and a higher temperature (>-98 °C) exalted the carbenoid nature of 2a, thus leading to the formation of enediols 4 (“eliminative dimerization”)18 and alkenes 5 which are the result of a “reductive alkylation” process promoted by s-BuLi on 2a with concomitant elimination of Li2O (Scheme 2).19 The reaction of (1S,2S)-2a with other electrophiles (CH3I,20 allyl bromide,21 and acetone) again occurred stereospecifically providing the corresponding R-substituted propylene oxides 3b-d in good yields and high dr and er values (Table 1). Interestingly, 2b, obtained by deprotonation of optically active (1S,2R)-(+)-1-phenylpropylene oxide 1b, proved to be more reactive with respect to the trans isomer 2a and configurationally stable. Under the same conditions as above, the deprotonation of 1b, at -98 °C, required only 30 min for completion, and the corresponding oxiranyllithium 2b was quantitatively deuterated (> 98% D) with complete retention of configuration at the R-carbon (Table 2).16 The temperature was also crucial: a temperature higher than -98 °C (e.g., -78 °C), even in the presence of 3 equiv of TMEDA, caused nucleophilic attack of s-BuLi and formation of products of the kind of 5. The observed configurational stability

(13) Castedo, L.; Castro, J. L.; Riguera, R. Tetrahedron Lett. 1984, 25, 1205-1208. (14) Shu, L.; Shi, Y. J. Org. Chem. 2000, 65, 8807-8810. (15) Foltz, C. M.; Witkop, B. J. Am. Chem. Soc. 1957, 79, 201-205. (16) (a) Deuterated 3a and 3e showed almost the same optical rotation of the starting epoxides 1a ([R]20D -44.8, c 1 CHCl3) and 1b ([R]20D +41.3, c 1 CHCl3), respectively. (b) Having used up to 3 equiv of s-BuLi and in consideration of the fact that unactivated epoxides can also undergo direct deprotonation (s-BuLi/TMEDA) to give destabilized oxiranyllithiums (Hodson, D. M.; Gras, E. Angew Chem., Int. Ed. 2002, 41, 2376-2378), we also checked enantiomeric purity of all the chiral nonracemic substituted phenylpropylene oxides synthesized, even if the dr would have been sufficient to ascertain the configurational stability of their lithiated precursors. (17) Marie´, J.-C.; Courillon, C.; Malacria, M. Synlett 2002, 4, 553556.

(18) (a) Boche, G.; Lohrenz, J. C. W. Chem. Rev. 2001, 101, 697756. (b) Lohse, P.; Loner, H.; Acklin, P.; Sternfeld, F.; Pfaltz, A. Tetrahedron Lett. 1991, 32, 615-618. (19) (a) Crandall, J. K.; Lin, L.-H. C. J. Am. Chem. Soc. 1967, 89, 4526-4527; (b) 1967, 89, 4527-4528. (c) Doris, E.; Dechoux, L.; Mioskowski, C. Tetrahedron Lett. 1994, 35, 7943-7946 and references therein. (d) Hogson, D. M.; Stent, M. A. H.; Wilson, F. X. Synthesis 2002, 1445-1453. (e) An NMR-spectroscopic study on lithiated phenylpropylene oxides is under way and will be reported in due course. (20) The preparation of only a mixture of the optically active transand cis-epoxides 3b/3f has been reported till now: Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224-11235. (21) Spectroscopic data of racemic trans-epoxide 3c have been reported in: Yano, K.; Hatta, Y.; Baba, A.; Matsuda, H. Synthesis 1992, 693-696.

b

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Capriati et al. TABLE 2. Reaction of (1S,2R)-2b with Electrophiles electrophile

product (% yield)a

convn (%)

D2O MeI Me2CO C6H5CONMe2

(1S,2R)-3e (>98) (2S,3R)-3f (84) (3S,4R)-3g (60) (2S,3R)-3h (70)e

>98 >98 80 >98

drb

erc

SCHEME 3

[R]20Dd

>98:2 >99:1 +38.0 ” ” +26.7 ” 99:1 +35.4 ” >99:1 +198.7

a Isolated yield after distillation or column chromatography. Diastereomeric ratio determined by 1H NMR analysis of the crude reaction mixture. c Enantiomeric ratio by GC analysis on a chiraldex B-DM capillary column or by 1H NMR analysis in the presence of a chiral solvating agent (see the Experimental Section). d c 1, CHCl . e In this case, 2 equiv of s-BuLi was used. 3 b

of cis-2b is worth noting as, in contrast to what was found by our group12a for lithiated cis-disubstituted oxazolinyloxiranes and by Molander22 for silicon-stabilized cis-tertbutyl-substituted oxiranyllithiums, the strain created in forcing the methyl and the phenyl groups both on the same side of the oxirane ring of 2b did not promote any interconversion between cis-2b and trans-2a. Moreover, the observed diastereo- and enantiospecificity was not time dependent. Indeed, deuteration of 2b at different reaction times (30 min and 2 h) gave only 3e with the same enantiomeric enrichment of the starting epoxide cis-1b. Equally highly stereospecific was the reaction with other electrophiles such as CH3I, acetone, and N,Ndimethylbenzamide; the corresponding R-adducts 3f-h were isolated in good yields and high dr and er values (Scheme 1, Table 2). Epoxides trans-2a and cis-2b also reacted smoothly with PhCHO leading in good yields to products 3i,j and 3k,l (Table 3), respectively, although with poor diastereoselectivity at the newly created stereogenic center: dr anti/syn 3i,j 70/30, dr anti/syn 3k,l 60/40. Stereoisomers could be separated by preparative HPLC and spectroscopically characterized. The assignment of syn (or anti)23 stereochemistry was made on the basis of the characteristic resonance of the carbinol proton: in the case of the syn isomer it was always shifted downfield compared to that of the anti isomer (δ 5.01 vs 4.99 for 3i and 3j; 4.93 vs 4.85 for 3k and 3l, respectively), as reported and demonstrated for similar epoxy alcohols derived from styrene oxide.12g The relative configuration (anti) of (()3j was also confirmed by crystallographic X-ray analysis.24 Moreover, the absolute configuration of (-)-3j and (+)-3l was ascertained to be that depicted in Table 3 by the modified Mosher method.25 Because of the overlapping of the aromatic proton resonances, we decided to use 19F NMR instead of 1H NMR; for this purpose, both the (R)- and (S)-2-methoxy-2-(trifluoromethyl)phenyl acetate (MTPA) esters were prepared. According to this procedure,25 when the bulkier substituent (e.g., L1, (22) Molander, G. A.; Mautner, K. Pure Appl. Chem. 1990, 62, 707712. (23) The convention employed for describing syn and anti diastereomers is as follows: if the main chain is written in an extended (zigzag) conformation, the diastereomer that has the oxiranyl ring and the hydroxy group both projecting either forward (bold bonds) or away from the viewer (dashed bonds) is called syn. (24) CCDC-232045 contains the supplementary crystallographic data for compound (()-3j. These data can be obtained free of charge at www.ccdc.ac.uk/conts/retrieving.html or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK.; Fax: (int) +44-1223/336-033; E-mail: [email protected]. (25) Seco, J. M.; Quin˜oa´, E.; Riguera, R. Chem. Rev. 2004, 104, 17117.

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Scheme 3) is on the same side as the phenyl group, the CF3 resonates at a higher field. For an alcohol having the configuration represented in Scheme 3, in which L1 is bulkier than L2, the sign of the parameter ∆δSR (19F)CF3 ) δCF3(S)-δCF3(R) would be negative. A ∆δSR < 0 was observed for both (-)-3j and (+)-3l (Scheme 3); these data allowed the absolute configuration at the carbinol carbons to be assigned as R thus supporting, at the same time, the above-presumed stereochemistry of these two epoxy alcohols (anti). The above epoxy alcohols 3i,j and 3k,l are interesting precursors of both erythro and threo aldols usually obtained by the Sharpless asymmetric epoxidation of allylic alcohols followed by a stereocontrolled rearrangement of the corresponding optically active epoxy silyl ethers, as reported.26 The stereoselective synthesis of R,β-epoxy alcohols is a challenging problem in synthetic organic chemistry: they are, indeed, excellent starting materials for the preparation of stereodefined polyols, natural products, or biologically active compounds.27 In view of this, we decided to study the carbonyl reduction of the R,β-epoxy ketone (()-3h.27 As can be seen in Table 4, the reduction of 3h with NaBH4/MeOH took place in good yield and reasonable anti diastereoselectivity. No stereoselective improvement was observed when the reduction with NaBH4 was carried out in the presence of Lewis acids such as CaCl2, ZnCl2, and CeCl3, thus excluding the possibility of a chelated cyclic transition state.28 The reduction with L-Selectride was even less diastereoselective. The observed anti diastereoselectivity could be accounted for with a modified Felkin-Ahn model29 by choosing the phenyl group as the “large” group not only for its bulkiness but also for having the lowest lying Csp3Csp2 σ* orbital.30 Of the two possible conformers depicted in Scheme 4, the most reactive one30 should be that in which the hydride ion attacks the carbonyl group (acti(26) Maruoka, K.; Sato, J.; Yamamoto, H. Tetrahedron 1992, 48, 3749-3762. (27) For a recent review on epoxy ketones as versatile building blocks in organic synthesis, see: Lauret, C. Tetrahedron: Asymmetry 2001, 12, 2359-2383. (28) (a) Taniguchi, M.; Fujii, H.; Oshima, K.; Utimoto, K. Tetrahedron 1995, 51 (3) 679-686. (b) Hojo, M.; Fujii, A.; Murakami, C.; Aihara, H.; Hosomi, A. Tetrahedron Lett. 1995, 36, 571-574. (c) Yun, J. M.; Sim, T. B.; Hahm, H. S.; Lee, W. K. J. Org. Chem. 2003, 68, 7675-7680. (29) Equilibrium geometry was preliminarily calculated for 3h and a systematic conformer distribution analysis was carried out at a semiempirical level (PM3) rotating about the CR-CdO bond. To introduce electron correlation in the computation of the energetics, the two local minimum-energy conformers found (corresponding just to those represented in Scheme 4 with the phenyl ring perpendicular to the CdO moiety) were subjected to single-point calculations using the density functional theory (DFT) at the B3LY/6-31 + G*//PM3 level of theory: the conformer having the oxiranyl oxygen anti to the CdO group, predicted to be the more reactive one, also resulted to be the more stable one of about 3.7 kcal/mol.

Synthesis of Optically Active Phenylpropylene Oxides TABLE 3. Reaction of (1S,2S)-2a and (1S,2R)-2b with PhCHO

substrate

producta (% yield)b

(1S,2S)-1a

(1S,2R,3S)-3i (52)e,f (1R,2R,3S)-3j (1S,2R,3R)-3k (85)g (1R,2R,3R)-3l

(1S,2R)-1b

erc

[R]20Dd

98:2

+69.4 -44.6 +20.6 +53.7

convn (%) 67 >98

”

a Absolute configuration ascertained as described. b Overall yields in both diastereoisomers after column chromatography. c Enantiomeric ratio by 1H NMR analysis in the presence of a chiral solvating agent (see the Experimental Section). d c 1, CHCl3. e dr anti/syn ) 70/30, separated by preparative HPLC. f In this case, 1.5 equiv of s-BuLi was used. g dr anti/syn ) 60/40, separated by preparative HPLC.

TABLE 4. Stereoselective Reduction of (()-3h with NaBH4 in MeOH

to the major adduct. Moreover, the coordination of borohydride by the oxiranyl oxygen in the transition state ST-2 ending with the anti isomer has also to be considered. Conclusion

reagenta

Tb (°C)

yield (%)c

convn (%)

anti/syn ratiod

NaBH4 NaBH4-CaCl2 NaBH4-CaCl2 NaBH4-ZnCl2 NaBH4-CeCl3 L-Selectride

-78 0 -78 ” ” ”e

86 70 65 64 90 50

97 97 95 63 >98 39

86:14 70:30 83:17 85:15 78:22 70:30

a (()-3h/NaBH /metal chloride molar ratio ) 1.0/1.0/2.0/2.0 4 according to the experimental procedure described in ref 28a; the above molar ratio was instead 1.0/2.0/1.5 in the case of the reduction using NaBH4 in the presence of ZnCl2, as reported in ref 28c. b The reaction time was always 30 min. c Overall yields in both diastereoisomers after column chromatography. d Diastereomeric ratio determined by 1H NMR analysis of the crude reaction mixture. e (()-3h/L-Selectride molar ratio ) 1.0/2.0, using THF as the solvent in this case, as reported in ref 28c.

SCHEME 4

vated by a hydrogen bonding with the MeOH) close to the oxiranyl oxygen; this “flight path” from the least hindered side should be the most favorable one leading (30) (a) Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353-3361. (b) Gawley, R. E.; Aube` J. In Principle of Asymmetric Synthesis; Baldwin, J. E., FRS, Magnus P. D., Eds.; Elsevier: New York, 1996.

In summary, this paper reports a new route to optically active phenylpropylene oxides. The observed high stereospecificity of the reactions of trans-2a and cis-2b with electrophiles can be reasonably ascribed to their configurational stability; moreover, it has been experimentally proved that cis-2b is more reactive than trans-2a. The coupling reaction with PhCHO leads to almost equimolar mixtures of the corresponding syn/anti epoxy alcohols, whereas the reduction with NaBH4 of the R-benzoyl cisepoxide 3h was markedly anti-stereoselective; a possible explanation for the observed diastereoselectivity has been also proposed. However, more work is needed and is underway, and results will be reported in due course.

Experimental Section Preparation of R-Substituted Phenylpropylene Oxides 3a-l. General Procedure. A solution of (1S,2S)-1a (150 mg, 1.12 mmol) and TMEDA (0.51 mL, 3.36 mmol) in 5 mL of dry THF at -98 °C (methanol/liquid nitrogen bath) and under N2 was treated with s-BuLi (2.58 mL, 3.36 mmol, 1.3 M), and the resulting deep red mixture was stirred for 2 h at this temperature. In the reaction of (1S,2S)-1a with PhCHO and of (1S,2R)-1b with PhCONMe2, 1.5 equiv and 2.0 equiv of s-BuLi were used, respectively. Then, the electrophile (3.36 mmol) was added at once as pure liquid or as a solution in 1 mL of THF if solid. The resulting reaction mixture was allowed to warm to room temperature and quenched with saturated aqueous NH4Cl. Then, it was poured into 20 mL of saturated brine, extracted with Et2O (3 × 10 mL), dried (Na2SO4), and concentrated in vacuo. The crude mixture was flash chromatographed (silica gel; petroleum ether/AcOEt 9-7/1-3) (or distilled by a Kugelrohr apparatus) and volatiles removed under reduced pressure by means of a Bu¨chi vacuum controller B-721 (240 mbar at 40 °C) to give the corresponding R-substituted propylene oxides, which showed the following data: (1S,2S)-(-)-1-Deutero-1-phenyl-1,2-epoxypropane (3a): colorless oil (bp 47 °C, 10-3 Torr); 77% yield; convn > 98%, > 98% D, dr >98:2, er >99:1 [tRmajor ) 20.64 min, tRminor ) 21.22 min on a Chiraldex B-DM (Astec) (30 m × 0.25 mm i.d. × 0.25

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Capriati et al. µm film thickness) capillary column, Det. FID 300 °C, column head pressure 12 psi, He flow 1.5 mL/min, split ratio 100/1, oven temperature 100 °C]; [R]20D ) -38.0 (c 1, CHCl3). (2S,3S)-(-)-2-Phenyl-2,3-epoxybutane (3b): colorless oil (bp 47 °C, 10-3 Torr); 51% yield; convn > 98%, dr >98:2, er >99:1 [tRmajor ) 4.22 min, tRminor ) 4.32 min on a Chiraldex B-DM (Astec) (30 m × 0.25 mm i.d. × 0.25 µm film thickness) capillary column, Det. FID 300 °C, column head pressure 12 psi, He flow 1.5 mL/min, split ratio 100/1, oven temperature 100 °C]; [R]20D ) -16.0 (c 1, CHCl3); 1H and 13C NMR have been reported in the case of (2R*,3R*)-3b in ref 20; GC-MS (70 eV) m/z 148 (49, M+), 147 (16), 133 (100), 119 (46), 104 (73), 103 (94), 91 (35), 78 (81), 65 (15); FT-IR (film, cm-1) 3059, 1448, 1383, 1277, 1071, 1028, 842, 775, 742, 700. (4S,5S)-(+)-4-Phenyl-4,5-epoxy-1-hexene (3c): colorless oil (bp 43 °C, 10-3 Torr); 74% yield; convn 98%, dr >98:2, er 97:3 [tRmajor ) 9.70 min, tRminor ) 10.04 min on a Chiraldex B-DM (Astec) (30 m × 0.25 mm i.d. × 0.25 µm film thickness) capillary column, Det. FID 300 °C, column head pressure 12 psi, He flow 1.5 mL/min, split ratio 100/1, oven temperature 100 °C]; [R]20D ) +6.6 (c 1, CHCl3); 1H and 13C NMR have been reported in the case of (4R*,5R*)-3c in ref 21; GC-MS (70 eV) m/z 174 (3, M+), 173 (11), 159 (11), 145 (17), 129 (67), 120 (30), 115 (48), 105 (100), 91 (16), 77 (36), 51 (12); FT-IR (film, cm-1) 3063, 1642, 1449, 1264, 990, 916, 748, 700. (3S,4S)-(+)-2-Methyl-3-phenyl-3,4-epoxypentan-2-ol (3d): colorless oil (bp 47 °C, 10-3 Torr); 51% yield; convn 83%, dr >98:2, er >99:1 [tRmajor ) 6.29 min, tRminor ) 6.13 min on a Chiraldex B-DM (Astec) (30 m × 0.25 mm i.d. × 0.25 µm film thickness) capillary column, Det. FID 300 °C, column head pressure 12 psi, He flow 1.5 mL/min, split ratio 100/1, oven temperature 100 °C]; [R]20D ) +7.0 (c 1, CHCl3); 1H NMR (300 MHz) δ: 1.06 (s, 3 H), 1.43 (s, 3 H), 1.73 (d, J ) 5.9 Hz, 3 H), 2.49 (s, 1 H, exchanges with D2O), 3.05 (q, J ) 5.9 Hz, 3 H), 7.24-7.37 (m, 5 H); 13C NMR (75 MHz) δ 12.7, 23.9, 28.6, 60.6, 68.5, 69.1, 125.8, 126.2, 126.5, 133.2; GC-MS (70 eV) m/z 174 (3, M+), 173 (11), 159 (11), 145 (17), 129 (67), 120 (30), 115 (48), 105 (100), 91 (16), 77 (36), 51 (12); FT-IR (film, cm-1) 3063, 1642, 1449, 1264, 990, 916, 748, 700. (1S,2R)-(+)-1-Deutero-1-phenyl-1,2-epoxypropane (3e): colorless oil (bp 47 °C, 10-3 Torr); >98% yield, convn > 98%, >98% D, dr >98:2, er >99:1 [tRminor ) 8.37 min, tRmajor ) 9.12 min on a Chiraldex B-DM (Astec) (30 m × 0.25 mm i.d. × 0.25 µm film thickness) capillary column, Det. FID 300 °C, column head pressure 12 psi, He flow 1.5 mL/min, split ratio 100/1, oven temperature 100 °C]; [R]20D ) +38.0 (c 1, CHCl3). (2S,3R)-(+)-2-Phenyl-2,3-epoxybutane (3f): colorless oil (bp 47 °C, 10-3 Torr); 84% yield; convn > 98%, dr >98:2, er >99:1 ascertained by 1H NMR (500 MHz, CCl4 with CDCl3 as external standard) in the presence of the chiral solvating agent (CSA) (R)-(-)-1-phenyl-2,2,2-trifluoroethanol (CSA/epoxide molar ratio ) 3/1) δ 1.74 (sminor, 3 H, CCH3Ph), 1.75 (smajor, 3 H, CCH3Ph); [R]20D ) +26.7 (c 1, CHCl3); 1H NMR (300 MHz) δ 0.98 (d, J ) 5.5 Hz, 3 H), 1.64 (s, 3H), 3.17 (q, J ) 5.5 Hz, 1 H), 7.24-7.34 (m, 5H); 13C NMR (125 MHz) δ 14.4, 24.5, 61.2, 62.6, 126.5, 127.0, 128.0, 138.6; GC-MS (70 eV) m/z 148 (26, M+), 147 (100), 133 (6), 104 (75), 91 (7), 78 (52), 77 (33), 63 (5), 51 (14), 43 (10); FT-IR (film, cm-1) 3030, 2967, 1605, 1445, 1376, 1259, 765, 702. (3S,4R)-(+)-2-Methyl-3-phenyl-3,4-epoxypentan-2-ol (3g): colorless oil (bp 47 °C, 10-3 Torr); 60% yield; convn 80%, dr >98:2, er 99:1 [tRminor ) 31.48 min, tRmajor ) 33.59 min on a Chiraldex B-DM (Astec) (30 m × 0.25 mm i.d. × 0.25 µm film thickness) capillary column, Det. FID 300 °C, column head pressure 12 psi, He flow 1.5 mL/min, split ratio 100/1, oven temperature 100 °C]; [R]20D ) +35.4 (c 1, CHCl3); 1H NMR (500 MHz) δ 0.96 (d, J ) 5.5 Hz, 3 H), 1.10 (s, 3 H), 1.32 (s, 3 H), 2.20 (s, 1 H, exchanges with D2O), 3.60 (q, J ) 5.5 Hz, 1 H), 7.24-7.31 (m, 5 H); 13C NMR (125 MHz) δ: 15.3, 25.4, 26.9, 55.9, 70.4, 70.8, 127.6, 135.9; GC-MS (70 eV) m/z 148 [M+ 44] (19), 134 (65), 133 (100), 115 (13), 105 (69), 91 (15), 77 (29),

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59 (13), 43 (13); FT-IR (film, cm-1) 3452, 2972, 1451, 1367, 1190, 958, 754, 704. (2S,3R)-(+)-2,3-Epoxy-1,2-diphenylbutan-1-one (3h): colorless oil (bp 47 °C, 10-3 Torr); 70% yield, convn >98%, dr >98: 2, er >99:1 [tRmajor ) 39.69 min, tRminor ) 40.47 min on a Chiraldex B-DM (Astec) (30 m × 0.25 mm i.d. × 0.25 µm film thickness) capillary column, Det. FID 300 °C, column head pressure 12 psi, He flow 1.5 mL/min, split ratio 100/1, oven temperature 150 °C]; [R]20D ) +198.7 (c 1, CHCl3); 1H NMR (500 MHz) δ 1.13 (d, J ) 5.5 Hz, 3 H), 3.57 (q, J ) 5.5 Hz, 1 H), 7.24-7.56 (m, 8 H), 8.03 (d, J ) 7.5 Hz, 2 H); 13C NMR (125 MHz) δ 13.4, 59.2, 68.6, 126.8, 128.3, 129.7, 129.8, 130.0, 133.2, 133.5, 134.2, 195.6; GC-MS (70 eV) m/z 238 (63, M+), 223 (7), 165 (55), 194 (2), 165 (55), 133 (20), 105 (100), 77 (57), 51 (15); FT-IR (film, cm-1) 3340, 3029, 2969, 1682, 1598, 1494, 1448, 1276, 1210, 971, 832, 700. (1S,2R,3S)-1-Phenyl-2,3-epoxybutan-1-ol (3i): colorless oil; 52% yield; convn 67%, er 98:2 ascertained by 1H NMR (500 MHz, CCl4 with CDCl3 as external standard) in the presence of the chiral solvating agent (CSA) (R)-(-)-1-phenyl-2,2,2trifluoroethanol (CSA/epoxide molar ratio ) 3/1) δ 1.84 (dmajor, J ) 6.0 Hz, 3 H, CHCH3), 1.85 (dminor, J ) 6.0 Hz, 3 H, CHCH3); [R]20D ) +69.4 (c 1, CHCl3); 1H NMR (500 MHz) δ: 1.72 (d, J ) 6.0 Hz, 3 H), 2.35 (d, J ) 4.0 Hz, 1 H, exchanges with D2O), 3.24 (q, J ) 6.0 Hz, 1 H), 5.01 (d, J ) 4.0 Hz, 1 H), 6.99-7.36 (m, 10 H); 13C NMR (125 MHz) δ: 14.9, 61.8, 68.2, 74.3, 126.1, 127.3, 127.5, 127.6, 128.1, 128.3, 136.7, 139.8; GC-MS (70 eV) m/z 222 [M+-H2O] (3), 196 (55), 167 (26), 152 (15), 134 (62), 133 (54), 105 (100), 91 (18), 77 (53), 51 (14), 43 (6); FT-IR (film, cm-1) 3445, 3031, 1496, 1448, 1027, 756, 712. (1R,2R,3S)-1-Phenyl-2,3-epoxybutan-1-ol (3j): colorless oil; 52% yield; convn 67%, er 98:2 ascertained by 1H NMR (500 MHz, CCl4 with CDCl3 as external standard) in the presence of the chiral solvating agent (CSA) (R)-(-)-1-phenyl-2,2,2trifluoroethanol (CSA/epoxide molar ratio ) 3/1) δ 1.81 (dmajor, J ) 5.5 Hz, 3 H, CHCH3), 1.82 (dminor, J ) 5.5 Hz, 3 H, CHCH3); [R]20D ) -44.6 (c 1, CHCl3); 1H NMR (500 MHz) δ 1.69 (d, J ) 6.0 Hz, 3 H), 2.32 (d, J ) 3.0 Hz, 1 H, exchanges with D2O), 3.20 (q, J ) 6.0 Hz, 1 H), 4.99 (d, J ) 3.0 Hz, 1 H), 7.11-7.24 (m, 10 H); 13C NMR (125 MHz) δ 13.9, 61.1, 66.4, 74.4, 126.5, 127.4, 127.5, 127.7, 127.8, 137.8, 139.9; GC-MS (70 eV) m/z 222 [M+ - H2O] (2), 196 (61), 167 (30), 165 (31), 152 (18), 134 (69), 133 (60), 105 (100), 91 (15), 77(53), 51 (13), 43 (3); FT-IR (film, cm-1) 3445, 3032, 1495, 1447, 1059, 756, 711. (1S,2R,3R)-1-Phenyl-2,3-epoxybutan-1-ol (3k): white solid; mp 147-148 °C (hexane); 85% yield; convn >98%, er 98:2 ascertained by 1H NMR (500 MHz, CCl4 with CDCl3 as external standard) in the presence of the chiral solvating agent (CSA) (R)-(-)-1-phenyl-2,2,2-trifluoroethanol (CSA/epoxide molar ratio ) 3/1) δ 1.14 (dminor, J ) 5.5 Hz, 3 H, CHCH3), 1.15 (dminor, J ) 5.5 Hz, 3 H, CHCH3); [R]20D ) +20.6 (c 1, CHCl3); 1H NMR (500 MHz) δ 0.99 (d, J ) 5.5 Hz, 3 H), 3.67 (q, J ) 5.5 Hz, 1 H), 4.93 (s, 1 H), 7.01-7.28 (m, 10 H); 13C NMR (125 MHz) δ 14.7, 57.2, 68.5, 76.0, 126.9, 127.4, 127.7, 127.8, 127.9, 128.1, 135.0, 140.1; GC-MS (70 eV) m/z 222 [M+ - H2O] (4), 196 (22), 165 (16), 134 (70), 133 (64), 105 (100), 91 (13), 77 (51), 51 (12); FT-IR (KBr, cm-1) 3467, 2927, 1447, 1134, 1069, 758, 709. Anal. Calcd for C16H16O2: C, 79.97; H, 6.71. Found: C, 80.22; H, 6.70. (1R,2R,3R)-1-Phenyl-2,3-epoxybutan-1-ol (3l): white solid; mp 95-96 °C (hexane); 85% yield; convn >98%, er 98:2 ascertained by 1H NMR (500 MHz, CCl4 with CDCl3 as external standard) in the presence of the chiral solvating agent (CSA) (R)-(-)-1-phenyl-2,2,2-trifluoroethanol (CSA/epoxide molar ratio ) 3/1) δ 1.17 (dminor, J ) 5.5 Hz, 3 H, CHCH3), 1.18 (dmajor, J ) 5.5 Hz, 3 H, CHCH3); [R]20D ) +53.7 (c 1, CHCl3); 1H NMR (500 MHz) δ 1.03 (d, J ) 5.5 Hz, 3 H), 3.62 (q, J ) 5.5 Hz, 1 H), 4.85 (s, 1 H), 6.96-7.28 (m, 10 H); 13C NMR (125 MHz) δ 14.8, 56.4, 68.5, 76.1, 127.6, 127.7, 128.0, 128.1, 128.3, 135.0, 139.0; GC-MS (70 eV) m/z 222 [M+ - H2O] (4), 196 (19), 178 (9), 167 (48), 134 (100), 133 (90), 105 (97), 91 (14), 77 (57), 51 (14), 43 (5); FT-IR (KBr, cm-1) 3415, 1456, 995, 926,

Synthesis of Optically Active Phenylpropylene Oxides 712, 696. Anal. Calcd for C16H16O2: C, 79.97; H, 6.71. Found: C, 80.36; H, 6.63.

Acknowledgment. This work was carried out under the framework of the National Project “Stereoselezione in Sintesi Organica, Metodologie ed Applicazioni” and the FIRB Project “Progettazione, preparazione e valutazione biologica e farmacologica di nuove molecole organiche quali potenziali farmaci innovativi” supported by the Ministero dell’Istruzione, dell’Universita` e della Ricerca (MIUR, Rome), and by the University of Bari. We are also grateful to Dr. Michel Giorgi of the Faculte´

des Sciences Saint-Je´roˆme (Laboratoire de Cristallochimie), Marseille, France, for performing X-ray analysis on compound (()-3j. Supporting Information Available: General experimental paragraph, copies of the 1H or 13C NMR spectra of compounds 3a,e (S3), 3b,c (S4), 3d,f (S5), 3g-j (S6-S7), and an ORTEP view of (()-3j (Figures S1). This material is available free of charge via the Internet at http://pubs.acs.org. JO035858W

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